Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis

Donizy,Piotr; Kaczorowski,Maciej; Leskiewicz,Marek; Zietek,Marcin; Pieniazek,Malgorzata; Kozyra,Cyprian; Halon,Agnieszka; Matkowski,Rafal

doi:10.3892/or.2014.3531

Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis

Authors:
- Piotr Donizy
- Maciej Kaczorowski
- Marek Leskiewicz
- Marcin Zietek
- Malgorzata Pieniazek
- Cyprian Kozyra
- Agnieszka Halon
- Rafal Matkowski
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Affiliations: Department of Pathomorphology and Oncological Cytology, Wrocław Medical University, 50‑556 Wrocław, Poland, Department of Statistics, Wrocław University of Economics, 53-345 Wrocław, Poland, Lower Silesian Oncology Centre, 53-413 Wrocław, Poland, Department of Oncology and Division of Surgical Oncology, Wrocław Medical University, 53-413 Wrocław, Poland
Published online on: October 6, 2014 https://doi.org/10.3892/or.2014.3531
Pages: 2735-2743

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Abstract

The presence of ulceration has been considered as one of the most important primary tumor characteristics of cutaneous malignant melanoma (CMM) for predicting patient outcome. Yet recently, scientific attention has been drawn towards another microscopic feature of primary tumors, the mitotic rate (MR). The present study aimed to examine the relationship between the presence of ulceration and the mitotic rate and clinicopathological characteristics and melanoma patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations. Tissue samples were obtained from 104 patients treated for CMM. In classical H&E staining, the mitotic rate and the presence of ulceration were evaluated. Non-mitogenic tumors were defined as having 0 mitoses/mm2, low mitogenic potential, 1-2 mitoses/mm2 and highly mitogenic tumors, ≥3 mitoses/mm2. In the entire group of 104 patients, a high mitotic rate (hMR) and ulceration were highly negative prognostic factors, and indicated considerably shorter overall survival, cancer-specific overall survival and disease-free survival. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in both the pT1 (P=0.001) and pT2 subgroups (P=0.006). Kaplan‑Meier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in the 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05). Multivariate analysis confirmed that hMR was strongly associated with an unfavorable prognosis. Ulceration had no prognostic significance in the Cox proportional hazards model. Considering the biology of melanoma, hMR seems to be a more reliable parameter than the presence of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases.

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1	Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: GLOBOCAN 2012 Cancer Incidence and Mortality Worldwide. IARC CancerBase V1.0. (11)International Agency for Research on Cancer; Lyon: 2013
2	Clark WH Jr, From L, Bernardino EA and Mihm MC: The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 29:705–727. 1969.PubMed/NCBI
3	Breslow A: Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 172:902–908. 1970. View Article : Google Scholar : PubMed/NCBI
4	Balch CM, Murad TM, Soong SJ, Ingalls AL, Halpern NB and Maddox WA: A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg. 188:732–742. 1978.PubMed/NCBI
5	Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH and Morabito A: Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 19:3622–3634. 2001.
6	Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ and Sondak VK: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 27:6199–6206. 2009. View Article : Google Scholar : PubMed/NCBI
7	Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA and Thompson JF: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 19:3635–3648. 2001.PubMed/NCBI
8	Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, Flaherty KT, Gimotty PA, Johnson T, Johnson MM, Leong SP, Ross MI, Byrd DR, Cascinelli N, Cochran AJ, Eggermont AM, McMasters KM, Mihm MC Jr, Morton DL and Sondak VK: Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 29:2199–2205. 2011. View Article : Google Scholar
9	Kesmodel SB, Karakousis GC, Botbyl JD, Canter RJ, Lewis RT, Wahl PM, Terhune KP, Alavi A, Elder DE, Ming ME, Guerry D, Gimotty PA, Fraker DL, Czerniecki BJ and Spitz FR: Mitotic rate as a predictor of sentinel lymph node positivity in patients with thin melanomas. Ann Surg Oncol. 12:449–458. 2005. View Article : Google Scholar : PubMed/NCBI
10	Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, Cascinelli N, Cochran AJ, Coit DG, Eggermont AM, Johnson T, Kirkwood JM, Leong SP, McMasters KM, Mihm MC Jr, Morton DL, Ross MI and Sondak VK: Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 28:2452–2459. 2010. View Article : Google Scholar
11	Azzola MF, Shaw HM, Thompson JF, Soong SJ, Scolyer RA, Watson GF, Colman MH and Zhang Y: Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 97:1488–1498. 2003. View Article : Google Scholar : PubMed/NCBI
12	Barnhill RL, Katzen J, Spatz A, Fine J and Berwick M: The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma. J Cutan Pathol. 32:268–273. 2005. View Article : Google Scholar : PubMed/NCBI
13	Francken AB, Shaw HM, Thompson JF, Soong SJ, Accortt NA, Azzola MF, Scolyer RA, Milton GW, McCarthy WH, Colman MH and McGovern VJ: The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up. Ann Surg Oncol. 11:426–433. 2004. View Article : Google Scholar : PubMed/NCBI
14	Spatz A, Stock N, Batist G and van Kempen LC: The biology of melanoma prognostic factors. Discov Med. 10:87–93. 2010.PubMed/NCBI
15	Zettersten E, Sagebiel RW, Miller JR III, Tallapureddy S, Leong SP and Kashani-Sabet M: Prognostic factors in patients with thick cutaneous melanoma (>4 mm). Cancer. 94:1049–1056. 2002. View Article : Google Scholar
16	Nagore E, Oliver V, Botella-Estrada R, Moreno-Picot S, Insa A and Fortea JM: Prognostic factors in localized invasive cutaneous melanoma: high value of mitotic rate, vascular invasion and microscopic satellitosis. Melanoma Res. 15:169–177. 2005. View Article : Google Scholar : PubMed/NCBI
17	Murali R, Haydu LE, Long GV, Quinn MJ, Saw RP, Shannon K, Spillane AJ, Stretch JR, Kefford RF, Thompson JF and Scolyer RA: Clinical and pathologic factors associated with distant metastasis and survival in patients with thin primary cutaneous melanoma. Ann Surg Oncol. 19:1782–1789. 2012. View Article : Google Scholar : PubMed/NCBI
18	Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP and Thompson JF: Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol. 30:2678–2683. 2012. View Article : Google Scholar : PubMed/NCBI
19	Han D, Zager JS, Shyr Y, Chen H, Berry LD, Iyengar S, Djulbegovic M, Weber JL, Marzban SS, Sondak VK, Messina JL, Vetto JT, White RL, Pockaj B, Mozzillo N, Charney KJ, Avisar E, Krouse R, Kashani-Sabet M and Leong SP: Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 31:4387–4393. 2013. View Article : Google Scholar : PubMed/NCBI
20	Eigentler TK, Buettner PG, Leiter U and Garbe C: Impact of ulceration in stages I to III cutaneous melanoma as staged by the American Joint Committee on Cancer Staging System: an analysis of the German Central Malignant Melanoma Registry. J Clin Oncol. 22:4376–4383. 2004. View Article : Google Scholar
21	Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ and Barnhill RL: Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer. 39:1861–1865. 2003. View Article : Google Scholar : PubMed/NCBI
22	Taylor RC, Patel A, Panageas KS, Busam KJ and Brady MS: Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol. 25:869–875. 2007. View Article : Google Scholar : PubMed/NCBI
23	Ostmeier H, Fuchs B, Otto F, Mawick R, Lippold A, Krieg V and Suter L: Can immunohistochemical markers and mitotic rate improve prognostic precision in patients with primary melanoma? Cancer. 85:2391–2399. 1999. View Article : Google Scholar : PubMed/NCBI
24	Niakosari F, Kahn HJ, McCready D, Ghazarian D, Rotstein LE, Marks A, Kiss A and From L: Lymphatic invasion identified by monoclonal antibody D2–40, younger age, and ulceration: predictors of sentinel lymph node involvement in primary cutaneous melanoma. Arch Dermatol. 144:462–467. 2008.
25	Balch CM, Wilkerson JA, Murad TM, Soong SJ, Ingalls AL and Maddox WA: The prognostic significance of ulceration of cutaneous melanoma. Cancer. 45:3012–3017. 1980. View Article : Google Scholar : PubMed/NCBI